Rivastigmine is prescribed for the treatment of mild to moderate Alzheimer's disease. The tartarate salt of Rivastigmine is marketed under brand name of Exelon®. Rivastigmine is in a class of medications called cholinesterase inhibitors. It improves mental function by increasing the amount of a certain natural substance in the brain. Rivastigmine increases the amounts of a chemical called acetylcholine in the brain. Acetylcholine may be involved in memory, attention, and learning.
U.S. Pat. No. 4,948,807 describes process for preparation of racemic Rivastigmine by reacting α-m-hydroxyphenylisopropyldimethylmine or α-m-hydroxyphenyl ethyldimethylmine with carbomyl chloride in the presence of NaH. Process for resolution of racemic Rivastigmine is described in U.S. Pat. No. 5,602,176, which involves resolution using di-o,o′-p-toluoyl tartaric acid. The major drawback of this process is repeated recrystallization in the final step to achieve increased enantiomeric excess, which results in decreased yield with increase in processing steps.
PCT publication no. WO03/101917 describes process for preparation of Rivastigmine by condensing N-ethyl-N-methyl-4-nitrophenyl carbamate, which is obtained from 4-nitrophenyl chloroformate, with [1-(3-hydroxyphenyl) ethyl]dimethylamine, which is obtained by demethylation of [1-(3-methoxyphenyl) ethyl]dimethylamine, in the presence of base. The process of preparation of [1-(3-hydroxyphenyl) ethyl]dimethylamine involves use of DL-methionine and 50% sulphuric acid. DL-methionine is a costly reagent and also a skin, eye and respiratory irritant
The process described in PCT publication no. WO2004/037771 involves reductive amination of 3-methoxy acetophenone in presence of dimethylamine, titanium isopropoxide and sodium borohydride to obtain [1-(3-methoxyphenyl)ethyl]dimethylamine, which is further demethylated using hydrobromic acid to obtain 3-(1-dimethylamino)phenol. This is further resolved using (S)-(+)-camphor-10-sulfonic acid and reacted with carbamoyl chloride to obtain Rivastigmine. Titanium isopropoxide and sodium borohydride are very expensive reagents which lead to increase in overall cost of the process. Moreover hydrobromic acid is hazardous in nature and thus making it difficult to handle at commercial scale.
The process for preparation of 3-(1-dimethylamino)phenol as described in PCT publication no. WO2006/068386 involves subjecting (S)-3-(1-dimethylaminoethyl)phenol to N-methylation using formaldehyde/formic acid. Further it is subjected to O-carbamoylation to obtain Rivastigmine. It was observed by the inventors of present invention that by process described here, the product obtained did not have desired physical properties and the yield of reaction was also poor.
Therefore there is a need to develop a process for preparation for preparation of Rivastigimine and its intermediates which is simple, cost effective, non-hazardous and commercially viable.